The present invention relates to N-(mercaptoalkyl)ureas and carbamates useful in the treatment of cardiovascular disorders and pain conditions.
Cardiovascular disorders which may be treated with compounds of the present invention include hypertension, congestive heart failure, edema and renal insufficiency.
Human hypertension represents a disease of multiple etiologies. Included among these is a sodium and volume dependent low renin form of hypertension. Drugs that act to control one aspect of hypertension will not necessarily be effective in controlling another.
Enkephalin is a natural opiate receptor agonist which is known to produce a profound analgesia when injected into the brain ventricle of rats. It is also known in the art that enkephalin is acted upon by a group of enzymes known generically as enkephalinases, which are also naturally occurring, and is inactivated thereby.
A variety of mercaptoacylamino acids are known as enkephalinase inhibitors useful as analgesics and in the treatment of hypertension. U.S. Pat. No. 4,774,256 discloses compounds of the formula ##STR2## wherein n is 1-15 and R.sub.2 and R.sub.3 are various aryl, arylalkyl and heteroarylalkyl groups. The compounds are disclosed as having enkephalinase inhibiting activity.
U.S. Pat. No. 4,801,609 to Haslanger et al discloses antihypertensive compounds of the formula ##STR3## wherein n is 0 or 1; R.sup.1 is substituted phenyl and R.sup.2 is substituted alkyl, phenyl or heteroaryl.
U.S. Pat. No. 4,513,009 to Roques et al discloses similar compounds and those having the formula ##STR4## wherein R.sup.1 includes alkyl and optionally substituted phenyl, n is 0 or 1 and R.sup.2 includes phenyl and substituted alkyl. The compounds are disclosed by Roques et al as principally having enkephalinase inhibitory activity, but are also said to be antihypertensives.
European Patent Application 161,769 discloses enkephalinase inhibitors of the formula ##STR5## wherein R.sub.2 includes alkyl, aryl and arylalkyl, R.sub.3 includes alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, and n is 1-15.
It is known that the heart secretes a series of peptide hormones called atrial natriuretic factors (ANF) which help to regulate blood pressure, blood volume and the excretion of water, sodium and potassium. ANF were found to produce a short-term reduction in blood pressure and to be useful in the treatment of congestive heart failure. See P. Needleman et al, "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid, Electrolyte and Blood-Pressure Homeostasis", N. Engl. J. Med., 3147, 13 (1986) pp. 828-834, and M. Cantin et al in "The Heart as an Endocrine Gland", Scientific American, 254 (1986) pg. 7681. U.S. Pat. No. 4,740,499 to Olins discloses a method of prolonging the effect of atrial peptides comprising co-administering thiorphan (a compound within the scope of U.S. Pat. No. 4,513,009) or kelatorphan with an atrial peptide.
A class of drugs known to be effective in treating some types of hypertension is ACE inhibitors, which compounds are useful in blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the formation of angiotensin II from angiotensin I. For a review of ACE inhibitors, see M. Wyvratt and A. Patchett, "Recent Developments in the Design of Angiotensin Converting Enzyme Inhibitors" in Med. Res. Rev. Vol. 5, No. 4 (1985) pp. 483-531.